POS1409 NEW INSIGHTS INTO THE ANTIPHOSPHOLIPID SYNDROME SPECTRUM: FROM ANTIPHOSPHOLIPID ANTIBODIES POSITIVE SUBJECTS PROFILING TO IDENTIFICATION OF SYSTEMIC APS SUBSET THROUGH TYPE I INTERFERON PATHWAY ACTIVATION
Authors: I. Cecchi, M. Radin, A. Barinotti, S. G. Foddai, E. Rubini, A. Suárez, D. Roccatello, S. Sciascia, J. Rodríguez-Carrio
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Type I Interferon (IFN) pathway activation plays a central role in the pathogenesis of several autoimmune conditions. However, limited evidence is available on the IFN pathway activation in antiphospholipid antibody (aPL) positive subjects, including aPL carriers and antiphospholipid syndrome (APS) patients. In addition, recent evidences have highlighted the existence of a bridging condition between pure primary APS (PAPS) and defined systemic lupus erythematosus (SLE) with higher general features, such as cytopenia and arthritis, which is known as <i>systemic APS</i><sup>[1]</sup> and needs further clarification. <h3>Objectives</h3> The aim of this study was to evaluate the differential expression of IFN stimulated genes (ISG) among different subsets of aPL positive subjects. <h3>Methods</h3> For the purpose of this study, 31 primary APS, 25 secondary APS (SAPS), 27 SLE patients without aPL, 29 aPL carriers <sup>[2,3]</sup> and 19 healthy controls (HCs) were recruited. Complete demographic, clinical, and laboratory data were collected at the time of the inclusion. <i>Systemic APS</i> was defined as in previous papers <sup>[1]</sup>. IFI6, IFI44, IFI44L, MX1, IFI27, OAS1 and RSAD2 gene expression was evaluated by RT-PCR in whole blood. Normalized gene expression levels (Z-scores) were averaged into a global IFN signature (IFN score). Differences were measured by Kruskal-Wallis tests, and associations among genes were studied by cluster, correspondence and network analyses. <h3>Results</h3> An overall IFN pathway activation was noted across APS subsets, but certain differences were noted among genes. Some genes were already upregulated in the aPL-positive group compared to HC (IFI44, IFI44L, MX1, IFI27, OAS1 and RSAD2, all p&lt;0.050), while others were only increased in SLE (IFI6). MX1 differed between SLE and SAPS, whereas IFI27 and OAS1 showed differences between PAPS and SAPS. The composite IFN score revealed quantitative differences across APS subsets, being elevated in aPL carriers/PAPS groups compared to HCs (both p&lt;0.050) and increasing in SAPS (p&lt;0.010) and SLE (p&lt;0.001). Network analyses (Figure 1A) revealed qualitative differences in the gene-gene correlation networks: (i) weaker structures were found in HCs and aPL carriers, compared to stronger and higher-degree networks in SAPS and SLE; and (ii) the influence of each node was different across groups. Unsupervised cluster analysis revealed 3 clusters (Figure 1B), whose usage differed across APS subsets, thus correlating clinical status (Figure 1C). <i>Systemic APS</i> (n=51) was hallmarked by a higher IFN pathway activation (p=0.032) which was attributed to the expression of certain genes (IFI6, IFI44, IFI44L and IFI27; all p&lt;0.050), compared to those without <i>systemic APS</i>. Gene-gene interactions also showed differences between subsets (Figure 1D). Individuals with <i>systemic APS</i> were more likely to use cluster III (p=0.042) (Figure 1E). <h3>Conclusion</h3> IFN pathway activation is a common hallmark among aPL-positive individuals as well as in <i>systemic APS</i>, in which a differential and unique expression of ISG has been observed. Qualitative and quantitative differences across the APS spectrum can be identified, leading to the identification of distinct IFN signatures with different clinical value beyond traditional categorization. <h3>Reference</h3> [1]Sciascia S, et al. Rheumatology (Oxford) (2021); 2. Miyakis S, et al. J Thromb Haemost (2006); 3. Aringer M, et al. Arthritis Rheumatol (2019) <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.